TY - JOUR
T1 - Gata3-deficient mice develop parathyroid abnormalities due to dysregulation of the parathyroid-specific transcription factor Gcm2
AU - Grigorieva, Irina V.
AU - Mirczuk, Samantha
AU - Gaynor, Katherine U.
AU - Nesbit, M. Andrew
AU - Grigorieva, Elena F.
AU - Wei, Qiaozhi
AU - Ali, Asif
AU - Fairclough, Rebecca J.
AU - Stacey, Joanna M.
AU - Stechman, Michael J.
AU - Mihai, Radu
AU - Kurek, Dorota
AU - Fraser, WD
AU - Hough, Tertius
AU - Condie, Brian G.
AU - Manley, Nancy
AU - Grosveld, Frank
AU - Thakker, Rajesh V.
PY - 2010/6/1
Y1 - 2010/6/1
N2 - Heterozygous mutations of GATA3, which encodes a dual zinc-finger transcription factor, cause hypoparathyroidism with sensorineural deafness and renal dysplasia. Here, we have investigated the role of GATA3 in parathyroid function by challenging Gata3+/– mice with a diet low in calcium and vitamin D so as to expose any defects in parathyroid function. This led to a higher mortality among Gata3+/– mice compared with Gata3+/+ mice. Compared with their wild-type littermates, Gata3+/– mice had lower plasma concentrations of calcium and parathyroid hormone (PTH) and smaller parathyroid glands with a reduced Ki-67 proliferation rate. At E11.5, Gata3+/– embryos had smaller parathyroid-thymus primordia with fewer cells expressing the parathyroid-specific gene glial cells missing 2 (Gcm2), the homolog of human GCMB. In contrast, E11.5 Gata3–/– embryos had no Gcm2 expression and by E12.5 had gross defects in the third and fourth pharyngeal pouches, including absent parathyroid-thymus primordia. Electrophoretic mobility shift, luciferase reporter, and chromatin immunoprecipitation assays showed that GATA3 binds specifically to a functional double-GATA motif within the GCMB promoter. Thus, GATA3 is critical for the differentiation and survival of parathyroid progenitor cells and, with GCM2/B, forms part of a transcriptional cascade in parathyroid development and function.
AB - Heterozygous mutations of GATA3, which encodes a dual zinc-finger transcription factor, cause hypoparathyroidism with sensorineural deafness and renal dysplasia. Here, we have investigated the role of GATA3 in parathyroid function by challenging Gata3+/– mice with a diet low in calcium and vitamin D so as to expose any defects in parathyroid function. This led to a higher mortality among Gata3+/– mice compared with Gata3+/+ mice. Compared with their wild-type littermates, Gata3+/– mice had lower plasma concentrations of calcium and parathyroid hormone (PTH) and smaller parathyroid glands with a reduced Ki-67 proliferation rate. At E11.5, Gata3+/– embryos had smaller parathyroid-thymus primordia with fewer cells expressing the parathyroid-specific gene glial cells missing 2 (Gcm2), the homolog of human GCMB. In contrast, E11.5 Gata3–/– embryos had no Gcm2 expression and by E12.5 had gross defects in the third and fourth pharyngeal pouches, including absent parathyroid-thymus primordia. Electrophoretic mobility shift, luciferase reporter, and chromatin immunoprecipitation assays showed that GATA3 binds specifically to a functional double-GATA motif within the GCMB promoter. Thus, GATA3 is critical for the differentiation and survival of parathyroid progenitor cells and, with GCM2/B, forms part of a transcriptional cascade in parathyroid development and function.
U2 - 10.1172/JCI42021
DO - 10.1172/JCI42021
M3 - Article
SN - 0021-9738
VL - 120
SP - 2144
EP - 2155
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -